Hormone Receptor-positive Metastatic Breast Research Articles

Future perspectives and challenges with CDK4/6 inhibitors in hormone receptor-positive metastatic breast cancer.

There are three US FDA-approved CDK4/6 inhibitors: palbociclib, ribociclib and abemaciclib for patients with HR-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). They are all equally effective, so the question becomes how to choose among these agents and how to sequence them. Other areas with active investigation include identifying predictive biomarkers for the selection of patients whom may benefit more from CDK4/6 inhibitors, deciding whether to continue CDK4/6 inhibitors after disease progression on CDK4/6 inhibitors, creating novel treatment combinations and expanding use beyond HR+/HER2- MBC. Here, we review the current use of and potential next directions for CDK4/6 inhibitors in the treatment of patients with HR+/HER2- MBC.

Abstract 4105: Co-existing ESR1 D538G mutation and ESR1-CCDC170 fusion in a patient with metastatic hormone receptor positive breast cancer with progression after hormonal therapy

Abstract Breast cancer has a high annual incidence among females in India, with an age adjusted rate of 25.8 cases per 100,000 women and a mortality rate of 12.7 per 100,000 women1. Approximately 75% of breast cancers are estrogen receptor positive (ER+), and unfortunately, a significant number will develop resistance to first line hormonal therapy. Although several mechanisms have been linked to hormonal therapy resistance, no biomarker in clinical use currently exists to predict hormonal therapy resistance in a reliable manner. Comprehensive genomic profiling (CGP) is not routinely performed for metastatic breast carcinoma (MBC) in a relapsed setting in India. This research highlights utility of CGP on a MBC sample combined with interpretation by Watson™ for Genomics (WfG), an artificial-intelligence (AI)-based decision-support system (DSS), when a patient in a middle-income country developed resistance to endocrine therapy. A 33-year-old Indian female was diagnosed with ER+, progesterone-receptor-negative (PR-), human-epidermal-receptor-2-negative (HER2-) breast cancer. Two years later, she noted an axillary mass which was biopsied and revealed an ER+, PR-, HER2- MBC metastasis. CGP was performed with a panel from Illumina designed to detect genomic alterations in 170 genes, including 148 genes for substitutions and indels, 55 genes for fusion and splice variants, and 59 genes for copy number variation detection. Variant annotation and interpretation performed using WfG revealed co-existing ESR1 D538G mutation and ESR1-CCDC170 fusion. In addition, alterations in CCND1 resulting in activation of the CDK signaling pathway, an oncogenic mutation in MTOR resulting in activation of the MTOR/PI3K signaling pathway, and amplification of FGFR1, a poor prognostic factor in MBC, were also identified. While ESR1 D538 and ESR1-CCDC170 fusion individually have been reported to confer resistance to endocrine therapy, to the best of our knowledge, our report is the first HR+ MBC case with these two oncogenic alterations co-occurring in a metastatic tumor suggesting a synergistic role. CGP in this patient revealed a possible mechanism of resistance to endocrine therapy informing the physician to change treatment to a generic mTOR inhibitor based on the oncogenic MTOR mutation. In conclusion, assessment of DNA/RNA tumor variants in one assay along with a robust AI-based DSS can provide relevant information for consideration by the clinician when developing a treatment plan, may create efficiencies in tumor sample usage, time, and cost of treatment. Further research is needed to explore the functional synergy of the oncogenic ESR1 mutation and fusion detected in this patient's tumor and the role of identifying these pathogenic variants through circulating tumor cell or cell-free DNA assays to detect minimal residual disease. Citation Format: Ravindra Kolhe, Ashis Mondal, Nikhil Sahajpal, Meenakshi Ahluwalia, Yull Arriaga, Allan Njau, David Brotman, Jane Snowdon, Gretchen Jackson, Dilhan Weeraratne. Co-existing ESR1 D538G mutation and ESR1-CCDC170 fusion in a patient with metastatic hormone receptor positive breast cancer with progression after hormonal therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4105.

Abstract 5366: Metastatic breast cancer subgroup specific mRNA profiles of circulating tumor cells and extracellular vesicles

Abstract Background: We recently demonstrated great differences in the RNA profiles of matched circulating tumor cells (CTCs) and extracellular vesicles (EVs) in HER2 negative (HER2-) hormone receptor positive (HR+) metastatic breast cancer (MBC) patients. To elucidate the clinical utility of CTC and EV RNA profiling, we here a) tested the RNA profiles of another MBC subgroup, namely the HER2 positive (HER2+) patients, and b) compared the profiles in the two cohorts. Patients and methods: Blood was collected from 25 HER2+ (HR+ and HR-) and 35 HER2- (only HR+) MBC patients at the time of disease progression and at two consecutive staging time points. CTCs were isolated from 5 ml blood by positive immunomagnetic selection targeting EpCAM, EGFR and HER2 (AdnaTest EMT2/StemCell Select). EVs were isolated from 4 ml pre-filtered plasma by affinity-based binding to a spin column (exoRNeasy). The mRNA was purified by Oligo-dT beads and reverse transcribed (AdnaTest EMT2/StemCell Detect). Pre-amplified cDNA was analyzed by multimarker qPCR assays (AdnaTest TNBC Panel prototype) for 18 genes (including AKT2, ALK, AR, AURKA, BRCA1, KIT, MET, EGFR, ERCC1, ERBB2, ERBB3, KRT5, mTOR, NOTCH1, PARP1, PIK3CA, SRC, GAPDH). Consumables: QIAGEN, Germany. Results: In the HER2+ cohort, transcripts involved in the PI3K pathway were significantly more prevalent in CTCs compared to EVs and were found in more than 50% of these patients. In contrast, NOTCH1 and PARP1 were significantly more prominent in EVs as compared to their matched CTCs and EV PARP1 and EV AURKA overexpression signals were detected in more than 50% of patients. ERCC1 and SRC signals were present in CTCs as well as EVs in the majority of patients. ERCC1 signals in CTCs and EVs showed a significantly higher frequency in the HER2+ compared to the HER2-HR+ cohort. However, ERCC1 signals in CTCs of the HER2-HR+ cohort correlated with shorter survival time after first diagnosis of metastasis (p=0.011). In general, the overexpression signal prevalence was similar in both cohorts and both blood analytes. A small overlap of identical signals in CTCs and EVs of 15%/5% in the HER2+/HER2-HR+ cohort was observed. Interestingly, ERBB2 signals were only found in CTCs, not EVs, and in both cohorts with a similar prevalence (36%/40%). ERBB3 overexpression signals in CTCs significantly correlated with non-response only in the HER2-HR+ cohort (p=0.021). However, in HER2+ patients ERBB3 signals were only present at the time of progressive disease, but not at the time point of stable disease. Conclusions: RNA profiling indicated great differences in CTCs and EVs in both subgroups. Moreover, data emphasize the immense diversity between HER2+ versus HER2-HR+ MBC patients, revealing the need for blood analyte specific and subgroup specific multimarker panel for therapy management based on liquid biopsies in the future. Citation Format: Corinna Keup, Siegfried Hauch, Mitra Tewes, Hans-Christian Kolberg, Oliver Hoffmann, Rainer Kimmig, Sabine Kasimir-Bauer. Metastatic breast cancer subgroup specific mRNA profiles of circulating tumor cells and extracellular vesicles [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5366.

ICON: a randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer

BackgroundImmunotherapy with checkpoint inhibitors (CPI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR + BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CPI combined with selected chemotherapy in patients with metastatic HR + BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use anthracycline, which are considered as “immunogenic” chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells.MethodsICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR + BC. Primary objectives are aassessment of toxicity and progression-free survival. The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1 mg intravenously every 6th week) + nivolumab (240 mg intravenously every 2nd week). Patients in arm A will be offered ipi + nivo after disease progression.DiscussionICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The cross-over patients from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represent the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy.Trial registration NCT03409198, Jan 24th 2018; https://clinicaltrials.gov/ct2/show/record/NCT03409198

RENATA study-Latin American prospective experience: clinical outcome of patients treated with palbociclib in hormone receptor-positive metastatic breast cancer-real-world use.

BackgroundIn hormone receptor-positive, HER-2 negative (HR+/HER2−) advanced breast cancer (ABC) endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in first and second line improved progression-free survival (PFS), overall response rate (ORR) and clinical benefit rate (CB) without deterioration in quality of life compared with ET alone. In addition, recent data showed improvement in overall survival (OS) for premenopausal women in first line setting and for different subgroups of patients in second line. Since 2015, in Argentina, the combination of ET with CDK4/6i is a standard of care in HR+/HER2− ABC.MethodsWe carried out a prospective analysis of real-world use of palbociclib with ET in HR+/HER2− ABC patients who received treatment between October 2015 and August 2019 in two private institutes from Buenos Aires, Argentina. The aims of the study were to determine efficacy and safety of patients treated with ET and palbociclib, describe patient profile and treatment strategy beyond progression.ResultsOne-hundred and twenty-eight patients were included in the final analysis. Main baseline characteristics include, median age 57 years, 20% were premenopausal women, 44% had visceral metastasis and 26% bone only disease. More than half of patients had two or more metastatic sites, 44.4% had performance status 1, and most of them (59.4%) were treated with palbociclib in first-line setting. Palbociclib was preferentially associated with aromatase inhibitors in 63.9% of patients, and with fulvestrant in the remaining. All premenopausal women received ovarian suppression or ovarian ablation (OS/OA). The median PFS was 36.7 months in first line and 24.2 months in second line. The ORR was 45.3% and 25.0% in first and second line, respectively. The median OS in the entire population was not reached. Half of patients did not require dose interruption and/or delay, dose reduction was required in 15% of patients and almost no patients required drug discontinuation (2.0%). With regard to safety, 55% of patients developed grade 3–4 adverse events, 20% neutropenia grade 3–4, and 7% febrile neutropenia. Infections were presented in one out of three patients, mostly uncomplicated.ConclusionsThis is the first prospective evidence of real-world use of palbociclib in a Latin American population. We found similar outcomes to the PALOMA-2 and PALOMA-3 randomised trials and Real-World Data already published, with lower incidence of side effects and treatment discontinuation, but with higher incidence of febrile neutropenia.

Use of alpelisib in the treatment of hormone receptor positive metastatic breast cancer: An institutional experience.

e15216 Background: Mutations in PI3K pathway is a known mechanism of resistance to endocrine therapy in breast cancer. Alpelisib is an alpha-specific PI3K inhibitor. Alpelisib with Fulvestrant is approved for treatment (Tx) of PIK3CA mutated HR+ metastatic breast cancer (MBC) that progress on hormonal therapy. Despite its approval by the FDA, real world data on the use of Alpelisib for the management of MBC is lacking. This abstract reviews the safety and efficacy of Alpelisib in the management of patients with MBC. Methods: A retrospective review of the tumor registry database at a single institution was conducted to identify patients with HR+ MBC. Detailed clinical and pathologic data of PIK3CA mutated patients treated with Alpelisib were obtained. Genomic profiling was done with Foundation One. Results: Table highlights the characteristics of the four patients. All were treated with Alpelisib and Fulvestrant after PIK3CA mutation was demonstrated. 3 patients were heavily pretreated with systemic Tx including CDK 4/6 inhibitors. All patients responded to Alpelisib and Fulvestrant despite treatment history. Mucositis, rash, hyperglycemia and pancytopenia were the observed adverse events (A/E). All A/E were adequately managed except in one patient that required discontinuation of Tx. None has clinically progressed. Conclusions: Our data suggests that Alpelisib and Fulvestrant is tolerated and improves outcomes in patients with HR+ MBC. Alpelisib and Fulvestrant could be an effective therapy in patients who have also progressed on systemic chemotherapy including CDK 4/6 inhibitors. Although our sample size is small, we hope that our experience could guide clinicians in the management of patients with HR+ MBC who harbor the PIK3CA mutation and are being treated with Alpelisib. [Table: see text]

Retrospective analysis of ribociclib and letrozole as first-line therapy in patients with hormone receptor (HR) positive metastatic breast cancer (MBC) within a managed access program (MAP) in Turkey.

e13055 Background: The combination of ribociclib with ET significantly increased progression free survival (PFS) and OS compared with ET in first line treatment of HR positive HER2 negative MBC. We aimed to evaluate the efficacy and safety of ribociclib and letrozole within Turkish MAP in order to present clinical outcome with the real-world use of ribociclib, outside of clinical trial setting. Methods: Turkish MAP enabled access to ribociclib in combination with letrozole as first-line therapy for MBC patients with HR positive and Her-2 negative tumors. Adequate bone marrow reserve, a normal QTc interval, normal renal and liver functions were required for eligibility. Patients received 600 mg ribociclib once daily for 3 wks followed by 1wk off. A retrospective chart review of patient demographics, clinical and treatment characteristics have been performed. Results: Between July and November 2017, 178 patients were included from 47 institutions in Turkey. We report the results of first 101 patients analyzed. The median age was 53 years (33–81 years) and median follow up was 16 months. Forty-six patients had de novo disease, 78% patients were postmenopausal, 22% had ovarian function suppression. Thirty-six % patients had adjuvant chemotherapy, 49% received adjuvant ET. Forty % had visceral disease. Thirty patients had grade 3 neutropenia, 3 patients had febrile neutropenia, 5 patients have grade 2-3 elevation of liver function tests. There was no QT prolongation. Dose reduction to 400 mg was required for 16 patients. Four patients discontinued ribociclib due to toxicity, 22 patients due to progression, one patient refused treatment. Twelve patients had complete remission as their best response. Median PFS was 24.12 months (95%CI 22.2-26.2). None of the clinical and pathologic factors were significantly associated with prolonged PFS. Conclusions: The efficacy and toxicity of first-line ribociclib and letrozole within Turkish MAP is similar to the results from randomized clinical studies for patients with HR positive, Her-2 negative MBC.

Radiomics risk score (RRS) on CT to predict survival and response to CDK 4/6 inhibitors in hormone receptor (HR) positive metastatic breast cancer (MBC).

e13041 Background: The addition of CDK 4/6 inhibitors (CDK) to endocrine therapy (ET) is the standard of care for HR+ MBC. Currently, no robust predictive markers for CDK inhibitors exist. We hypothesized that baseline imaging features on pre-treatment CT scans using machine learning could correctly identify responders to CDK. Methods: From a retrospective pt registry, 46 pts with HR+ MBC who received palbociclib (palbo) plus ET and had liver metastases were identified, and divided at random into equally sized training and testing cohorts. Patients with objective response/stable disease per RECIST v1.1 were defined as ‘responders’ (65%), and those with progressive disease within 6 months were ‘non-responders’ (35%). The median age at diagnosis was 62. All pts were ER+ and 4% were HER2+. 65% pts received palbo as 1st or 2nd line tx. 503 radiomic texture features measuring subtle differences in lesion heterogeneity on a pixel level were extracted on pre-treatment CT within the first lesion measured for RECIST assessment. An elastic net Cox proportional hazards model was constructed within the training set to derive a Radiomics Risk Score (RRS), which was evaluated for association with prognosis and response within the testing set. A risk score threshold was chosen in the training set for stratifying patients into high and low risk groups. Results: The RRS consisted of 4 radiomic features indicating intratumoral heterogeneity to be associated with poor outcome. In the independent testing set (n = 23), RRS was continuously associated with survival (p = .0027) on multivariate analysis, along with age and RECIST response (Table). Categorical risk groups were similarly associated with survival in the testing set (p = .00491, HR = 4.03, CI = 0.6772). Median survival time in low and high risk groups were 2.33 and 0.673 years, respectively. When compared against RECIST response in the testing set, RRS was found to also be predictive of response with an ROC curve of 0.675. Conclusions: Radiomics analysis was able to predict response and survival in HR+ MBC pts prior to initiation of treatment with CDK. [Table: see text]

Circulating Tumor Cells in Metastatic Breast Cancer: Clinical Applications and Future Possibilities

Circulating tumor cells (CTCs) have gained importance as an emerging biomarker in solid tumors in the last two decades. Several detection assays have been introduced by various study groups, with EpCAM-based CellSearch system being the most widely used and standardized technique. In breast cancer, detection of CTCs correlates with clinical outcome in early and metastatic settings. CTC persistence beyond first cycle of palliative chemotherapy indicates poor response to treatment in metastatic situation. Beyond prognostication and therapy monitoring, CTC counts can guide treatment decisions in hormone receptor positive HER2-negative metastatic breast cancer. Furthermore, CTC-based therapy interventions are currently under investigation in clinical trials. In this review, we focus on the current state of knowledge and possible clinical applications of CTC diagnostics in patients with metastatic breast cancer.

Different associations of tumor PIK3CA mutations and clinical outcomes according to aspirin use among women with metastatic hormone receptor positive breast cancer

IntroductionThe relationships among PIK3CA mutations, medication use and tumor progression remains poorly understood. Aspirin use post-diagnosis may modify components of the PI3K pathway, including AKT and mTOR, and has been associated with lower risk of breast cancer recurrence and mortality. We assessed time to metastasis (TTM) and survival with respect to aspirin use and tumor PIK3CA mutations among women with metastatic breast cancer.MethodsPatients with hormone receptor positive, HER2 negative (HR+/HER2-) metastatic breast cancer treated in 2009–2016 who received tumor genotyping were included. Aspirin use between primary and metastatic diagnosis was extracted from electronic medical records. TTM and survival were estimated using Cox proportional hazards regression.ResultsAmong 267 women with metastatic breast cancer, women with PIK3CA mutated tumors had longer TTM than women with PIK3CA wildtype tumors (7.1 vs. 4.7 years, p = 0.008). There was a significant interaction between PIK3CA mutations and aspirin use on TTM (p = 0.006) and survival (p = 0.026). PIK3CA mutations were associated with longer TTM among aspirin non-users (HR = 0.60 95% CI:0.44–0.82 p = 0.001) but not among aspirin users (HR = 1.57 0.86–2.84 p = 0.139). Similarly, PIK3CA mutations were associated with reduced mortality among aspirin non-users (HR = 0.70 95% CI:0.48–1.02 p = 0.066) but not among aspirin users (HR = 1.75 95% CI:0.88–3.49 p = 0.110).ConclusionsAmong women who develop metastatic breast cancer, tumor PIK3CA mutations are associated with slower time to progression and mortality only among aspirin non-users. Larger studies are needed to confirm this finding and examine the relationship among aspirin use, tumor mutation profile, and the overall risk of breast cancer progression.

Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors.

Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for PIK3CA mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.

BPI20-022: Use of Cyclin Dependent Kinase 4/6 Inhibitors in Hormone Receptor Positive HER2 Negative Metastatic Breast Cancer. Experience in a Third Level Hospital in Mexico City

"BPI20-022: Use of Cyclin Dependent Kinase 4/6 Inhibitors in Hormone Receptor Positive HER2 Negative Metastatic Breast Cancer. Experience in a Third Level Hospital in Mexico City" published on 20 Mar 2020 by National Comprehensive Cancer Network.

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer.

Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

Abstract P3-08-50: Genome-wide association study predict prognosis of hormone receptor positive metastatic breast cancer in premenopausal women with endocrine therapy

Abstract Introduction: According to phase II clinical trial of endocrine treatment for hormone receptor positive (HR+) metastatic breast cancer(MBC) after tamoxifen treatment in premenopausal women, fulvestrant plus goserelin (F+G) has better clinical outcome than goserelin (G) alone in premenopausal women, in terms of time to progression (TTP). However, aromatase inhibitor (AI) with goserelin (A+G) is not superior to goserelin alone. Among three treatment arms, difference of overall survival (OS) was not observed. Accompanied with this clinical trial, we conducted further genotyping to identify alleles at some genomic loci associated with clinical outcome of endocrine treatments in premenopausal women with HR+ MBC. Methods: This prospective genotyping study included patients enrolled in a randomized phase II clinical trial of fulvestrant plus goserelin versus anastrozole plus goserelin versus goserelin alone for HR+, human epidermal growth factor receptor 2(HER2)-negative tamoxifen-pretreated premenopausal women with recurrent or metastatic breast cancer (KCSG BR10-04). To isolate genomic DNA from peripheral blood leukocytes, we used the Wizard Genomic DNA Purification Kit according to the manufacturer’s instructions (Promega, WI) and Axiom Precision Medicine Research Array (PMRA) (ThermoFisher, CA) was used to genotyping array. Survival analyses for time-to-progression (TTP) and overall survival (OS) were performed using the Kaplan-Meier method. To determine the association between clinical outcomes and single nucleotide polymorphisms (SNPs), we used an R package for genome-wide survival analysis (gwasurvivr). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for univariate and multivariate analyses. Finally, SNPs with adjusted p-value <0.05 were selected and used for survival analysis. Results: Of 138 participants, genomic DNA was collected and extracted from 127 participants. After quality control (QC), 103 genomic DNA were finally selected for genotyping (35 in F+G, 36 in A+G and 32 in G group). Patients with age under 40 were 34 (33%) and visceral metastases were observed in 50 patients (49%). Medial TTP was 16.3 months (95% confidence interval (CI): 13.3, 19.3) and median OS was 59.6 months (95% CI: 41.1, 78.1). Among 523,289 SNPs, 76 SNPs were associated with TTP (adjusted p-value <0.05, respectively). Of 76 SNPs, 47 were in coding lesions including ELF3, ARHGEF3, FOXP2, NTRK2, XPO5 and PI3KC2A. Other 29 were in non-coding lesions. In terms of OS, 13SNPs were associated and eleven were in coding lesions (ZMYM4, GRM7, ERC2, LEKR1, C3orf700, CEP135, ZNF827, LOC285692, DNAH11, FLJ42102 and LOC283440). Conclusions: Genetic polymorphisms influenced the clinical outcome of HR+ MBC patients treated with anti-hormonal therapy. Further studies on the functional mechanisms relating to these SNPs in these genes are warranted. Citation Format: Ji-Yeon Kim, Seock-Ah Im, Kyung Hae Jung, Keun Seok Lee, Joohyuk Sohn, Jee Hyun Kim, Hae Hyun Jung, Minjoo Lee, Young-Hyuck Im. Genome-wide association study predict prognosis of hormone receptor positive metastatic breast cancer in premenopausal women with endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-50.

Abstract P1-19-30: Safety results from a phase 2 study of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer

Abstract Background: Palbociclib is a reversible, oral, small molecule inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6). Palbociclib combined with various endocrine agents showed significantly improved progression-free survival in patients with metastatic hormone receptor-positive (HR+) breast cancer (MBC). Preclinical data demonstrates synergy for the combination of tamoxifen and palbociclib and that the combination is effective in a model of acquired tamoxifen resistance. Tamoxifen is an effective treatment for HR+ MBC and presents a different toxicity profile when compared with aromatase inhibitors and fulvestrant. Combining palbociclib with tamoxifen in first line treatment of HR+ MBC offers an alternative to other endocrine combinations. Methods: This is a non-randomized, open-label, single-arm, multicenter, phase II study of palbociclib in combination with tamoxifen in patients with HR+/HER2-negative advanced BC. The primary objective is to determine the objective response rate (complete or partial response) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease). Secondary objectives are: safety and tolerability, progression-free survival, clinical benefit rate, 2-year overall survival. Correlative objectives will explore alterations in circulating tumor DNA and changes in gene expression pattern at the time of progression. Safety assessments were performed at baseline, days 1 and 15 (first 2 cycles) and day 1 with each subsequent cycles. Adverse events (AEs) were graded according to NCI-CTCAE v4. Results: Forty-nine patients from 6 academic centers were enrolled in this trial at the time of this report. Baseline demographics and disease characteristics are reported in the table. Median age was 60 (range 39-82). Twenty-three (47%) patients presented with de-novo metastatic disease. Out of 26 (53%) patients who presented with recurrent metastatic disease, 13 (50%) were receiving adjuvant treatment with aromatase inhibitors at the time of recurrence and 13 (50%) were on surveillance with no active treatment. The most common drug related grade ≥ 3 AE was neutropenia (46%) that was transient and manageable by dose modifications, with no development of febrile neutropenia. The most common drug-related any grade AEs were neutropenia (68%), fatigue (43%), nausea (41%), anemia (32%), minor infections (30%), thrombocytopenia (29%), hot flashes (27%), lymphocytopenia (16%), alopecia (11%), diarrhea (11%).Two patients developed thromboembolic events (grades 2 and 4) and discontinued treatment. One patient died while on treatment. Conclusions: The combination of palbociclib and tamoxifen was well tolerated with expected toxicities. Neutropenia was the most frequently reported AE. This is one of the first trials to assess safety of the combination of palbociclib with tamoxifen in HR+ MBC and has implications for the early stage setting. Baseline Demographics and Disease CharacteristicsParameterN%SexFemale49100RaceWhite3367Black or African American1123Asian12American Indian or Alaska Native12Unknown36EthnicityHispanic or Latino36Non-Hispanic4694ECOG Performance status0336711531212Menopausal statusPost-menopausal4082Pre-menopausal918Site of metastasesBone3878Liver1326Lung816Other2245Bone only510 Citation Format: Oana C Danciu, Kent Hoskins, Cristina Truica, Anne Blaes, Deimante Tamkus, Jatin Rana, Tandra Pavankumar, Lauren Green, Li Liu, Menggang Yu, Deborah Toppmeyer, Ruth O'Regan, Kari Wisinski. Safety results from a phase 2 study of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-30.

Abstract OT2-02-01: A 'real world' experience of CDK4/6 inhibition with ribociclib and endocrine therapy in hormone receptor positive metastatic breast cancer in Australia

Abstract Background: The combination of CDK 4/6 inhibition and endocrine therapy has emerged as the new first line standard of care treatment for patients with hormone receptor (HR) +ve metastatic breast cancer (MBC)1. Ribociclib plus letrozole has been shown to improve PFS (25.3 vs 16.0 months; log-rank P=9.63x10-8) compared to letrozole alone2. More recently, this benefit has also been demonstrated in pre- and peri-menopausal women in combination with ovarian suppression and tamoxifen or an aromatase inhibitor (AI), with an improved overall survival (40.9 months vs OS not reached; HR = 0.712; p=0.00973) in the MONALEESA-7 study3. Approximately 800 patients in Australia participated in the ribociclib medicine access program (MAP) between May 2017 and June 2018, prior to government funding. Beyond eligibility criteria for the program and clinician name, no patient data was initially captured, consistent with usual practice for MAPs, due to the multiple challenges related to ethics, data ownership, security and patient privacy. We have previously demonstrated the feasibility of successful data collection alongside MAPs4 which can yield benefits for clinicians, industry and the broader medical community. Based on this we plan to retrospectively collect data for patients treated as part of the Australian ribociclib MAP. Trial Design: This is a secondary data use, non-interventional study of patients in Australia who received treatment with the combination of an AI and ribociclib, obtained via a MAP, for HR+ HER2- MBC. The target sample size is 250 patients from ~15 sites. De-identified patient data will be retrieved from the patient’s medical records and entered on to an electronic case report form. Data collection is anticipated to commence in July 2019 with the final treatment and survival outcomes collected in late 2020, thus allowing for a minimum of 24 month follow up for all patients from the start date of treatment with ribociclib and AI (May 2017 - June 2018). Study Aims: The primary aim of the study is to describe real world clinical and tumour characteristics of patients with HR+ HER2-ve MBC in Australia who are recommended and received ribociclib in combination with an aromatase inhibitor in the first line setting. Details of adjuvant therapy received and the tolerability of the treatment combination including dose interruptions, dose reductions and significant adverse events of interest related to ribociclib will be assessed. Secondary aims include time to treatment progression and progression free survival for the ribociclib and AI combination, and to explore the disease course post progression, including clinician choice of subsequent lines of therapy in routine clinical practice.

Abstract PD8-04: Ultra-deep multigene profiling of matched primary and metastatic hormone receptor positive breast cancer patients relapsed after adjuvant endocrine treatment reveals novel aberrations in the estrogen receptor pathway

Abstract Introduction: Although recent large-scale efforts1,2 have examined the mutational landscape of hormone receptor positive (HR+) metastatic breast cancer (mBC), identifying enriched alterations in such context, most analyses have considered prevalently metastatic samples, comparing them with either unmatched primary cases from the same institutions or large early breast cancer (eBC) sequencing databases. Hence, the statistical power to identify de novo somatic mutations and copy number aberrations (sCNAs) and the biological interpretation of findings have been limited, as have the associations with specific adjuvant treatment subgroups. Patients and methods: We collected primary and metastatic formalin-fixed, paraffin-embedded (FFPE) samples, as well as a source of germline DNA, from 204 HR+ BC cases undergoing adjuvant endocrine treatment (ET) for their disease after chemotherapy when indicated, and relapsing at least six months after surgery, with complete clinical follow-up concerning therapy for the early stage of patients’ disease and first line treatment information. We sequenced samples with a bespoke NGS panel encompassing 134 BC-specific genes, comparing mBC with matched eBC samples after filtering for germline variants, and associating our findings with adjuvant therapy and first line treatment. We performed multi-color fluorescence in-situ hybridization (m-FISH) to validate selected sCNAs. Results: We retrieved and successfully sequenced matched eBC, mBC, and germline DNA samples for 132 HR+ BC patients with complete clinical annotation. Mean sequencing depth for somatic and germline sequenced samples was in excess of 3,000x and 1,000x, respectively. On top of confirming the enrichment of mBC in ESR1, as well as MAPK pathway and transcriptional factor somatic aberrations, we identified and validated the presence of de novo amplifications of ESR1 and CYP19A1, the gene encoding for the aromatase protein. To our knowledge, this is the first high-confidence report from an NGS cohort of eBC/mBC cases concerning de novo amplifications in the estrogen receptor pathway genes in HR+ patients relapsed after adjuvant ET, as well as the largest described matched HR+ eBC/mBC case set undergoing ultradeep multigene profiling with complete clinical annotation. Associations with treatment and outcome variables will be presented at the meeting.

Abstract P1-19-12: Patterns of treatment with everolimus and exemestane in hormone receptor positive HER2 negative metastatic breast cancer in the era of targeted therapy

Abstract Background: In 2012 the FDA approved everolimus and exemestane (EE) as second line therapy for patients who have progressed on letrozole or anastrozole, based on the BOLERO-2 trial which showed improvement in PFS with EE compared to exemestane alone (6.9 vs 2.8 months). Currently, aromatase inhibitors (AI), or fulvestrant (F), alone or in combination with a CDK4/6 inhibitor (CDK4/6i) are the most commonly used first line endocrine therapies for hormone receptor (HR) positive HER2 negative metastatic breast cancer (mBC). There is currently no clinical trial data regarding the efficacy of EE in patients previously treated with CDK4/6i. The goal of this project was to explore the treatment patterns of EE in this contemporary patient population, with particular interest in those who had received prior CDK4/6i plus AI/F, as first, second, or third-line treatment. Methods: The Flatiron Health electronic health record-derived nationwide database selected de-identified patients with HR positive HER2 negative mBC and the first (1L), second (2L), and third line (3L) treatments they received. Duration of treatment (DOT) is defined as time from the date of initiation of a line of treatment to the day prior to initiation of subsequent line of treatment; prolonged DOT is defined as duration ≥ 6 months. Medical non-cancer co-morbidities listed as defined by the Charlson Comorbidity Index were included. Median DOT was compared using t-test, unadjusted for patient and disease characteristics. Statistical analysis was performed using Python v3.7. Results: A total of 8457 HR positive HER2 negative patients diagnosed with mBC between 1/2011 and 1/2019 were identified. Of these, 726 patients received EE in 1L (N=127), 2L (N=326), or 3L (N=273). In this cohort, 72.3% of patients were diagnosed between 2011-2014, and 27.7% were diagnosed after 1/2015, and most (94.6%) were treated in the community setting. The majority were female (98.4%), Caucasian (75.1%), and had no co-morbidities (79%); the mean age was 64. A quarter of patients (25%) had de novo mBC. The median DOT for 1L EE was 7.6 months (95% CI 5.6, 9.6); 56.7% received 1L EE for ≥6 months. The median DOT for 2L EE was 9.1 months (95% CI 7.6,10.6) following 1L AI/F and 10.7 months (95% CI 8.5,12.9) following 1L AI/F plus CDK4/6i (p<0.02). Over half (52%) of patients received 2L EE for ≥6 months following 1L AI/F, and 32% received 2L EE for ≥6 months following 1L AI/F plus CDK4/6i (p<0.005). The median DOT for 3L EE was 5.6 months (95% CI 3.8, 7.3) following 2L AI/F 2L vs 4.1 months (95% CI 3.1, 5.0) following 2L AI/F plus CDK4/6i (p<0.01). 48.5% received 3L EE for ≥6 months following 2L AI/F vs 34.2% following 2L AI/F plus CDK4/6i (p=0.06). Conclusion: In a cohort of patients with HR positive HER2 negative mBC who received EE in the 2L or 3L, a significant percentage of patients derived clinical benefit (DOT>6 months) from EE, even after CDK4/6i therapy. Patients who received CDK4/6i 1L had longer unadjusted DOT of 2L EE compared to those who received 1L AI/F alone. NMedian DOT (mo), 95% CIProlonged DOT (%)1L EE1277.6 (95% CI 5.6, 9.6)56.7%1L AI/F→2L EE2009.1 (95% CI 7.6, 10.6)52.0%1L AI/F + CDK4/6i→2L EE5010.7 (95% CI 8.5, 12.9)32.0%2L AI/F→3L EE995.6 (95% CI 3.8, 7.3)48.5%2L AI/F + CDK4/6i→3L EE734.1 (95% CI 3.1, 5.0)34.2% Citation Format: Mariya Rozenblit, Lajos Pusztai, Kerin Adelson, Sarah Mougalian. Patterns of treatment with everolimus and exemestane in hormone receptor positive HER2 negative metastatic breast cancer in the era of targeted therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-12.

Abstract P3-09-16: Fecal microbiome and association with outcomes among patients (pts) receiving eribulin (E) +/- pembrolizumab (P) for hormone receptor positive (HR+) metastatic breast cancer (MBC)

Abstract Background: Recent studies in murine models and humans suggest that modulation of the gut microbiome may enhance response to immune checkpoint blockade in different cancer types. However, little is known about the landscape of gut microbiome in pts with HR+ MBC and its influence on response to chemotherapy and immunotherapy.Methods: A randomized phase 2 trial of E +/- P for pts with HR+ MBC (n= 88) was conducted. The results of this study have been previously presented and found the addition of P did not result in an improvement in progression-free survival (PFS). Fecal samples were prospectively collected (baseline (BL), after 2 cycles of therapy (C2), and end of treatment (EOT)) in a subset of pts (E+P, n = 12; E, n = 11) in order to evaluate if microbiome was associated with response (partial response [PR], stable disease [SD], and progressive disease [PD]), PFS, and overall survival (OS). 16S rRNA gene sequencing was performed to characterize the diversity and composition of fecal microbiome. Results: A total 23 pts provided 23 BL, 22 C2, and 5 EOT fecal specimens for microbiome profiling. 16S(v3-4) rRNA gene data was successfully generated for all samples and the dataset was rarefied to 24,743 reads for analysis. Overall, the variability in the composition and structure of the fecal microbiome was significantly driven by each individual (p<0.001) more than any other variable studied. This effect was observed across all timepoints collected. At BL, subjects randomized to receive E+P and E did not show any differences in composition (p = 0.715) and structure (p = 0.457) of the fecal microbiome. The major genera identified in E+P and E groups were Bacteroides, 37.9% vs. 41.56%; Faecalibacterium 9.9% vs. 4.4%, and Blautia 4.9% vs. 2.9%, respectively. These abundances were observed at a similar level in the C2 sample. Overall, subjects receiving E had a marked increase in Faecalibacterium from 6.4% at BL to 21.2% at C2 and a decrease in Akkermansia from BL (8.5%) to C2 (<1%). Among those pts receiving E who achieved a PR, the abundance of Faecalibacterium increased from BL (4.3%) to C2 (13.9%), while the levels remained unchanged in those achieving SD. These shifts in abundance were not observed in the group receiving E+P. Subjects with PFS below the median had comparable alpha-diversity scores to those above the median in both arms of the study. Specifically, the number of Operational Taxonomic Units (OTUs) observed at BL in pts receiving E+P with PFS above and below the median were 563 and 663, respectively. When looking at the differences between BL and C2, OTUs decreased slightly to 513 and 637, respectively. Similar results were observed in pts receiving E. Among pts with PFS time below the median receiving E, there was a decrease in Akkermansia from BL (5.7%) to C2 (<1%). Pts with OS below the median had comparable alpha-diversity scores at BL to those above the median OS in both arms of the study. Pts with OS above the median receiving E experienced a decrease in the abundance of Akkermansia from BL (5.3%) to C2 (2.4%). Conclusion: The composition and structure of the fecal microbiome identified in this study were found to be associated primarily with the pt rather than with any of the variables studied including type of treatment and outcome. Although the fecal microbiome from all pts randomized were indistinguishable at BL, shifts in the abundance of certain types of bacteria like Faecalibacterium and Akkermansia were observed from BL to C2. These shifts were characteristic of pts receiving E but not of those receiving E+P. Although this study is limited by the small sample size in each arm, these findings warrant further evaluation in a larger population to interrogate if the composition and metabolic potential of the fecal microbiome can be used as a predictor of benefit to treatment. Citation Format: Romualdo Barroso de Sousa, Nadim Ajami, Tanya E Keenan, Chelsea Andrews, Jessica L Pittenger, Gerburg Wulf, Laura Spring, Ian E Krop, Eric P Winer, Elizabeth A Mittendorf, Sara M Tolaney. Fecal microbiome and association with outcomes among patients (pts) receiving eribulin (E) +/- pembrolizumab (P) for hormone receptor positive (HR+) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-16.

Abstract P3-12-01: Addition of capecitabine to maintenance endocrine therapy after induction therapy with bevacizumab plus paclitaxel in hormone receptor positive and HER2 negative metastatic breast cancer (KBCSG-TR1214)

Abstract Background: In the International Consensus Conference Guidelines for Advanced Breast Cancer, most experts agreed that the maintenance endocrine therapy after induction chemotherapy was reasonable. The combination therapy of bevacizumab (B) and paclitaxel (P) has proved to prolong progression free survival (PFS) and improve response rate in E2100 and MERiDiAN study for advanced and metastatic breast cancer (AMBC). Because of its long PFS, developing optimal therapeutic strategy of B+P to improve survival, including management of toxicity is crucial. However, it has not been assessed what therapy is optimal as maintenance therapy or how effective B+P re-challenge after failure of maintenance therapy is. Methods: In this multi-center randomized phase II study (KBCSG-TR1214), we compared endocrine therapy alone (E) and endocrine therapy with capecitabine (E+C) as a maintenance therapy after the induction chemotherapy with B+P. .Hormone receptor (HR)-positive and HER2-nagative patients who have experienced none or one prior chemotherapy for AMBC were enrolled. Patients without progression in 4-6 cycles of B+P were randomized to arm E (with E) or arm E+C (with E+C). In both arms, endocrine agents were decided by physician’s choice and in arm E+C, capecitabine (1657mg/m2 on day1 to 21 q4w) was added to E. After progression of either maintenance therapies, B+P started again as a re-challenge therapy. Primary end point was progression free survival (PFS) of maintenance therapy. Secondary end points include time to failure of strategy from randomization (TFS), efficacy of re-challenge therapy, overall survival (OS) and safety of induction therapy. Results:116 patients were enrolled until April 2016. 90 patients had been successful to shift to randomization. Median age was 59.8 years-old (34-81). 28 (60.9%) of 46 patients in arm E and 27 (61.4%) of 44 patients in arm E+C were administrated by aromatase inhibitor (AI) or AI+LH-RH analog. Median PFS of maintenance therapy was significantly longer in arm E+C (11.3month, 95%CI; 8.0-11.8) than in arm E (4.3months, 95%CI; 3.6-6.0) (HR:0.53, p=0.0054). Clinical benefit rate was 50.0% in arm E and 72.7% in arm E+C (p=0.0320). Median PFS, objective response rate and clinical benefit rate of P+B as re-challenge therapy following either E or E+C were 7.8months (95%CI; 6.7-9.5), 20.4% and 63.0%, respectively. There was a strong trend of improvement in OS at 24 months from randomization in arm E+C (73.0%) compared with in arm E (53.1%) (p=0.0524). We have not observed any new adverse toxicity profile regarding to E or E+C. Conclusions: Adding capecitabine to maintenance endocrine therapy was demonstrated to improve PFS and OS. To our knowledge, this is the first clinical trial to show the efficacy of endocrine therapy combined with metronomic chemotherapy as maintenance therapy after induction chemotherapy in HR-positive and HER2-negative AMBC patients. The concept of induction-maintenance could be a new therapeutic strategy for ABMC. (UMIN000008662). Citation Format: Tetsuhiro Yoshinami, Takahiro Nakayama, Masahiko Ikeda, Makiko Mizutani, Miki Yamaguchi, Yoshifumi Komoike, Tsutomu Takashima, Katsuhide Yoshidome, Junji Tsurutani, Mitsuhiko Iwamoto, Fumie Fujisawa, Hiroyuki Yasojima, Jun Yamamura, Hirotaka Morishima, Fuminori Aki, Tomomi Yamada, Satoshi Morita, Norikazu Masuda. Addition of capecitabine to maintenance endocrine therapy after induction therapy with bevacizumab plus paclitaxel in hormone receptor positive and HER2 negative metastatic breast cancer (KBCSG-TR1214) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-12-01.